Pyrazolopyrazine compound pharmaceutical use thereof

ABSTRACT

A pyrazolopyrazine compound of the following formula (I).  
                 
 
     wherein  
     R 1  is hydrogen or a suitable substituent; and  
     R 2  is hydrogen or halogen,  
     or a salt thereof.  
     The pyrazolopyrazine compound (I) and salt thereof of the present invention are adenosine antagonists and are useful for the prevention and/or treatment of depression, dementia (e.g. Alzheimer&#39;s disease, cerebrovascular dementia, dementia accompanying Parkinson&#39;s disease, etc.), Parkinson&#39;s disease, anxiety, pain, cerebrovascular disease (e.g. stroke, etc.), heart failure and the like.

TECHNICAL FIELD

[0001] The present invention relates to a novel pyrazolopyrazinecompound and a salt thereof, which are useful as medicaments.

BACKGROUND ART

[0002] Some pyrazolopyridine compounds to be useful as psychostimulant,remedy for renal failure, or the like are known (e.g. EP-0299209,EP-0379979, EP-0467248, EP-0516941, etc.). Pyrazolopyrazine compoundshaving pyridazine group to be adenosine antagonists are also known(WO00/69464). However, pyrazolopyrazine compounds having pyridine groupare novel, so there has been no knowledge about these compounds.

DISCLOSURE OF INVENTION

[0003] The present invention relates to a novel pyrazolopyrazinecompound and a pharmaceutically acceptable salt thereof, which areuseful as medicaments; processes for the preparation of saidpyrazolopyrazine compound and a salt thereof; a pharmaceuticalcomposition comprising, as an active ingredient, said pyrazolopyrazinecompound or a pharmaceutically acceptable salt thereof; a use of saidpyrazolopyrazine compound or a pharmaceutically acceptable salt thereofas a medicament; and a method for using said pyrazolopyrazine compoundor a pharmaceutically acceptable salt thereof for therapeutic purposes,which comprises administering said pyrazolopyrazine compound or apharmaceutically acceptable salt thereof to a human being or an animal.

[0004] The pyrazolopyrazine compound and a salt thereof are adenosineantagonists (especially, A₁ receptor and A₂ (particularly A2a) receptordual antagonists) and possess various pharmacological actions such asanticatalepsy action, cognitive enhancing action, analgesic action,locomotor action, antidepressant action, diuretic action,cardioprotective action, cardiotonic action, vasodilating action (e.g.cerebral vasodilating action, etc.), the action of increasing the renalblood flow, renal protective action, improvement action of renalfunction, enhancing action of lipolysis, inhibition action ofanaphylactic bronchoconstriction, acceleration action of the insulinrelease, the action of increasing the production of erythropoietin,inhibiting action of platelet aggregation, or the like.

[0005] They are useful as cognitive enhancer, antianxietry drug,antidementia drug, psychostimulant, analgesic, cardioprotective agent,antidepressant, ameliorants of cerebral circulation, tranquilizer, drugfor heart failure, cardiotonic agent, antihypertensive agent, drug forrenal failure (renal insufficiency), drug for renal toxicity, renalprotective agent, drug for improvement of renal function, diuretic, drugfor edema, antiobesity, antiasthmatic, bronchodilator, drug for apnea,drug for gout, drug for hyperuricemia, drug for sudden infant deathsyndrome (SIDS), ameliorants of immunosuppressive action of adenosine,antidiabetic agent, drug for ulcer, drug for pancreatitis, drug forMeniere's syndrome, drug for anemia;

[0006] drug for thrombosis, drug for myocardial infarction, drug forobstruction, drug for arteriosclerosis obliterans, drug forthrombophlebitis, drug for cerebral infarction, drug fortransientischemic attack, drug for angina pectoris, or the like;

[0007] and useful for the prevention and/or treatment of depression,dementia (e.g. Alzheimer's disease, cerebrovascular dementia, dementiaaccompanying Parkinson's disease, etc.), Parkinson's disease, anxiety,pain, cerebrovascular disease (e.g. stroke, etc.), heart failure;

[0008] hypertension (e.g. essential hypertension, nephrogenoushypertension, etc.);

[0009] circulatory insufficiency (acute circulatory insufficiency)cuased by, for example, ischemia/reperfusion injury (e.g. myocardialischemia/reperfusion injury, cerebral ischemia/reperfusion injury,peripheral ischemia/reperfusion injury, etc.), shock (e.g. endotoxinshock, hemorrhagic shock, etc.), surgical procedure, or the like;post-resuscitation asystole;

[0010] bradyarrhythmia;

[0011] electro-mechanical dissociation;

[0012] hemodynamic collapse;

[0013] SIRS (systemic inflammatory response syndrome);

[0014] multiple organ failure;

[0015] renal failure (renal insufficiency) (e.g. acute renal failure,etc.), renal toxicity [e.g. renal toxicity induced by a drug such ascisplatins, gentamicin, FR-900506 (disclosed in EP-0184162), cyclosporin(e.g. cyclosporin A) or the like; glycerol, etc.], nephrosis, nephritis,edema (e.g. cardiacedema, nephrotic edema, hepatic edema, idiopathicedema, drug edema, acute angioneurotic edema, hereditary angioneuroticedema, carcinomatous ascites, gestational edema, etc.);

[0016] obesity, bronchial asthma, gout, hyperuricemia, sudden infantdeath syndrome, immunosuppression, diabetes, ulcer suchaspeptic ulcer(e.g. gastric ulcer, duodenal ulcer, etc.), pancreatitis, Meniere'ssyndrome, anemia, dialysis-induced hypotension, constipation, ischemicbowel disease, ileus (e.g. mechanical ileus, adynamic ileus, etc.); and

[0017] myocardial infarction, thrombosis (e.g. arterial thrombosis,cerebral thrombosis, etc.), obstruction, arteriosclerosis obliterans,thrombophlebitis, cerebral infarction, transient ischemic attack, anginapectoris, or the like.

[0018] The novel pyrazolopyrazine compound of the present invention canbe shown by the following formula (I).

[0019] wherein

[0020] R¹ is hydrogen or a suitable substituent; and

[0021] R² is hydrogen or halogen,

[0022] or a salt thereof.

[0023] The object compound (I) and a salt thereof of the presentinvention can be prepared by the following processes.

[0024] wherein R² is as defined above,

[0025] R^(1a) is a suitable substituent;

[0026] R³ is lower alkyl; and

[0027] X is a leaving group.

[0028] The starting compound(II) or a salt thereof is novel and can beprepared, for example, by the following reaction schemes.

[0029] wherein R² and R³ are as defined above;

[0030] R⁴ is arylsulfonyl which may have one or more suitablesubstituent(s) or lower alkylsulfonyl;

[0031] Y is halogen;

[0032] Z⁻ is an anion.

[0033] In addition to the processes as mentioned above, the objectcompound (I) and a salt thereof can be prepared, for example, accordingto the procedures as illustrated in Examples in the presentspecification or in a manner similar thereto.

[0034] The starting compounds can be prepared, for example, according tothe procedures as illustrated in Preparations in the presentspecification or in a manner similar thereto.

[0035] The object compound (I) and a salt thereof can be preparedaccording to the methods as shown in Preparations or Examples, or in amanner similar thereto.

[0036] It is to be noted that the object compound (I) may include thegeometrical isomer(s) due to the double bond(s) and/or the stereoisomer(s) due to the asymmetric carbon atom(s). In this regard, oneisomer can be converted to another according to a conventional method inthis field of the art.

[0037] It is also to be noted that the solvating form of the compound(I) (e.g. hydrate, etc.) and any form of the crystal of the compound (I)are included within the scope of the present invention.

[0038] Suitable salts of the object compound (I) are conventionalpharmaceutically acceptable ones and include a metal salt such as analkali metal salt (e.g. sodium salt, potassium salt, etc.) and analkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), anammonium salt, an organic base salt (e.g. trimethylamine salt,triethylamine salt, pyridine salt, picoline salt, dicyclohexylaminesalt, N,N′-dibenzylethylenediamine salt, etc.), an organic acid salt(e.g. acetate, trifluoroacetate, maleate, tartrate, fumarate,methanesulfonate, benzenesulfonate, formate, toluenesulfonate, etc.), aninorganic acid salt (e.g. hydrochloride, hydrobromide, hydriodide,sulfate, phosphate, etc.), a salt with an amino acid (e.g. arginine,aspartic acid, glutamic acid, etc.), and the like.

[0039] Suitable examples and illustrations of the various definitionswhich the present invention includes within the scope thereof and whichappear in the above and following description in the presentspecification are explained in detail as follows.

[0040] Suitable example of “substituent” for R¹ is selected from thegroup consisting of lower alkyl, ar(lower)alkyl or cyclo(lower)alkylwhich may be interrupted by an oxygen atom.

[0041] The term “lower” is intended to mean 1 to 6 carbon atom(s) unlessotherwise indicated.

[0042] Suitable “lower alkyl” may include straight or branched ones suchas methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl orthe like, in which the preferred one may be (C1-C4)alkyl and the morepreferred one may be methyl, ethyl, propyl or isopropyl.

[0043] Suitable “cyclo(lower)alkyl” may be cyclo(C3-C8)-alkyl suchascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl or the like, in which the preferred one may be cyclo(C5-C7)alkyl such as cyclopentyl, cyclohexyl orcycloheptyl.

[0044] Said “cyclo(lower)alkyl” maybe interrupted by an oxygen atom, inwhich the preferred one may be saturated 3-8-membered heteromonocyclicgroup containing an oxygen atom such as tetrahydrofuranyl ortetrahydropyranyl.

[0045] Suitable “ar(lower)alkyl” may include phenyl(lower)alkyl (e.g.benzyl, phenethyl, etc.), diphenyl (lower)alkyl (e.g. benzhydryl, etc.),triphenyl(lower)alkyl (e.g. trityl, etc.), naphthyl(lower)alkyl,indenyl(lower)alkyl or anthryl(lower)alkyl and the like, in which thepreferred one may be phenyl(lower)alkyl, and the more preferred one maybe phenyl(C1-C4)alkyl.

[0046] Suitable “halogen” may include fluoro, chloro, bromo and iodo.

[0047] Suitable “a leaving group” may include halogen as mentionedabove, hydroxy, acyloxy such as alkanoyloxy (e.g. acetoxy, propionyloxy,etc.),sulfonyloxy (e.g. mesyloxy, tosyloxy, etc.), and the like.

[0048] Suitable “anion” may be formate, acetate, trifluoroacetate,maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate,chloride, bromide, iodide, sulfate, phosphate, or the like.

[0049] Suitable “arylsulfonyl” may include phenylsulfonyl,tolylsulfonyl, naphthylsulfonyl and the like, and said “arylsulfonyl”may have one or more (preferably 1 to 3) suitable substituent(s) such aslower alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy,tert-butoxy, pentyloxy, hexyloxy, etc.), aforesaid halogen, or the like.

[0050] Suitable “lower alkylsulfonyl” may include methylsulfonyl,ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl,tert-butylsulfonyl and the like, in which the preferred one may bemethylsulfonyl.

[0051] The processes for preparing the object pyrazolopyrazinecompound(I) are explained in detail in the following.

[0052] Process 1

[0053] The compound (Ia) or a salt thereof can be prepared by subjectingthe compound (II) or a salt thereof to hydrolysis.

[0054] Suitable salt of the compound (II) can be referred to an acidaddition salt as exemplified for the compound (I).

[0055] This reaction is carried out in accordance with a conventionalmethod.

[0056] The hydrolysis is preferably carried out in the presence of abase or an acid including Lewis acid.

[0057] Suitable base includes an inorganic base and an organic base suchas an alkali metal (e.g. sodium, potassium, etc.), an alkaline earthmetal (e.g. magnesium, calcium, etc.), the hydroxide or carbonate orhydrogencarbonate thereof, trialkylamide (e.g. trimethylamine,triethylamine, etc.), hydrazine, picoline,1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane,1,8-diazabicyclo[5.4.0]undec-7-ene, or the like.

[0058] Suitable acid includes an organic acid (e.g. formic acid, aceticacid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.)and an inorganic acid (e.g. hydrochloric acid, hydrobromic acid,sulfuric acid, hydrogen chloride, hydrogen bromide, etc.).

[0059] The elimination using Lewis acid such as BBr₃, BCl₃, BF₃, AlCl₃,TiCl₄ or the like is preferably carried out in the presence of cationtrapping agents (e.g. anisole, phenol, etc.).

[0060] The reaction is usually carried out in a solvent such as water,an alcohol (e.g. methanol, ethanol, isopropyl alcohol, etc.),tetrahydrofuran, dioxane, toluene, methylene chloride, ethylenedichloride, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide, orany other organic solvents which do not adversely affect the reaction,or a mixture thereof.

[0061] A liquid base or acid can be also used as the solvent. Thereaction temperature is not critical and the reaction is usually carriedout under cooling to heating.

[0062] Process 2

[0063] The compound (Ib) or a salt thereof can be prepared by reactingthe compound (Ia) or a salt thereof with the compound (III) or a saltthereof.

[0064] Suitable salt of the compound (Ia) can be referred to an acidaddition salt as exemplified for the compound (I).

[0065] Suitable salt of the compound (III) can be referred to the onesas exemplified for the compound (I).

[0066] The present reaction may be carried out in a solvent such aswater, phosphate buffer, acetone, chloroform, acetonitrile,nitrobenzene, methylene chloride, ethylene chloride, formamide,N,N-dimethylformamide, methanol, ethanol, sec-butanol, amyl alcohol,diethyl ether, dioxane, tetrahydrofuran, dimethyl sulfoxide, or anyother organic solvent which does not adversely affect the reaction,preferably in ones having strong polarities. Among the solvents,hydrophilic solvents may be used in a mixture with water. When thecompound (III) is in liquid, it can also be used as a solvent. Thereaction is preferably conducted in the presence of a base, for example,inorganic base such as alkali metal hydroxide (e.g. sodium hydroxide,potassium hydroxide, etc.), alkali metal carbonate, alkali metalbicarbonate, alkali metal hydride (e.g. sodium hydride), alkali metalalkoxide (e.g. EtONa, t-BuOK, etc.) organic base such as trialkylamine,and the like.

[0067] The reaction temperature is not critical, and the reaction isusually carried out at ambient temperature, under warming or underheating.

[0068] The present reaction is preferably carried out in the presence ofalkali metal halide (e.g. sodium iodide, potassium iodide, etc.), alkalimetal thiocyanate (e.g. sodium thiocyanate, potassium thiocyanate,etc.), di(lower)alkyl azodicarboxylate (e.g. diethyl azodicarboxylate,diisopropyl azodicarboxylate, etc.) or the like.

[0069] When X is —OH, activation of OH with triphenylphosphine and thelike may be necessary.

[0070] Process A

[0071] Step 1

[0072] The reaction of this step can be carried out by the methoddisclosed in Preparation 3 mentioned later or the similar mannersthereto.

[0073] Step 2

[0074] The compound (VIII) or a salt thereof can be prepared by reactingthe compound. (VI) or a salt thereof with the compound (VII) or a saltthereof.

[0075] Suitable salts of the compounds (VI), (VII) and (VIII) can bereferred to acid addition salts as exemplified for the compound (I).

[0076] The reaction is usually carried out in a solvent such as water,methylene chloride, ethylene chloride, N,N-dimethylformamide or anyother solvent which does not adversely influence the reaction or amixture thereof.

[0077] The reaction can be carried out in the presence of a base such asalkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide,etc.), alkalimetal carbonate, alkalimetal bicarbonate, alkali metalhydride (e.g. sodium hydride), alkali metal alkoxide (e.g. EtONa,t-BuOK, etc.) organic base such as trialkylamine,ar(lower)alkyltri(lower)alkylammonium halide (e.g.benzyltrimethylammonium chloride, etc.) or the like.

[0078] The reaction temperature is not critical and the reaction isusually carried out under cooling, at room temperature or under warming.

[0079] Step 3

[0080] The reaction of this step can be carried out by the methoddisclosed in Preparation 5 mentioned later or the similar mannersthereto.

[0081] The object compound (I) of the present invention is anadenosineantagonist and possesses the various pharmacological actions as statedbefore.

[0082] In order to show the usefulness of the compound (I) of thepresent invention, the pharmacological test result of the representativecompound of the present invention is shown in the following.

[0083] Test 1: Adenosine Antagonistic Activity

[0084] [I] Test Method

[0085] The adenosine antagonistic activity [Ki(nM)] of the test compoundwas examined by radioligand binding techniques using8-cyclopentyl-1,3-dipropylxanthine, [dipropyl-2,3-³H(N)] ([³H]DPCPX, 4.5nM) for human A₁ receptor and [³H]CGS 21680 (20 nM) for human A_(2a)receptor.

[0086] [II] Test Compound

[0087] 3-(2(1H)-Pyridinon-5-yl)-2-phenylpyrazolo[1,5-a]pyrazine (Example1)

[0088] 3- (1-Methyl-2(1H)-pyridinon-5-yl)-2-phenylpyrazolo[1,5-a]pyrazine (Example 2)

[0089] 3-(1-Ethyl-2(1H)-pyridinon-5-yl)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyrazine (Example 9)

[0090] [III] Test Result TABLE 1 Adenosine receptor Test compoundbinding (Ki:nM) (Example No.) A₁ A_(2a) 1 0.18 0.68 2 0.35 3.28 9 0.364.44

[0091] Test 2: Anticatalepsy Activity in Mouse

[0092] [I] Test Method

[0093] The test compound (3.2 mg/kg) was administered orally with ddYmice (n=7). Then, haloperidol (0.32 mg/kg) was injectedintraperitoneally 30 min. after the administration of the compound.Thirty min. after the injection, the cataleptic responses of mice weremeasured. The forelimbs of each mouse were placed on a 3 cm high, 3 mmwide horizontal bar, and the duration of cataleptic posture was measuredfor up to 30 sec.

[0094] [II] Test Compound

[0095] 3-(2(1H)-Pyridinon-5-yl)-2-phenylpyrazolo[1,5-a]pyrazine (Example1)

[0096] 3- (1-Methyl-2(1H)-pyridinon-5-yl)-2-phenylpyrazolo[1,5-a]pyrazine (Example 2)

[0097] 3-(1-Ethyl-2(1H)-pyridinon-5-yl)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyrazine (Example 9)

[0098] [III] Test Result TABLE 2 Test compound Manifestation rate ofcatalepsy (Example No.) (number of mouse) 1 1/7 2 0/7 9 0/7

[0099] The pyrazolopyrazine compound (I) and a salt thereof of thisinvention are useful as adenosine antagonists (especially, A₁ receptorand A₂ (particularly A_(2a)) receptor dual antagonists) and for theprevention and/or the treatment of depression, dementia (e.g.Alzheimer's disease, cerebrovascular dementia, dementia accompanyingParkinson's disease, etc.), Parkinson's disease, anxiety, pain,cerebrovascular disease, heart failure, hypertension, circulatoryinsufficiency, post-resuscitation, asystole, bradyarrhythmia,electro-mechanical dissociation, hemodynamic collapse, SIRS (systemicinflammatory response syndrome), multiple organ failure, renal failure(renal insufficiency), renal toxicity, nephrosis, nephritis, edema,obesity, bronchial asthma, gout, hyperuricemia, sudden infant deathsyndrome, immunosuppression, diabetes, ulcer, pancreatitis, Meniere'ssyndrome, anemia, dialysis-induced hypotension, constipation, ischemicbowel disease, ileus, myocardial infarction, thrombosis, obstruction,arteriosclerosis obliterans, thrombophlebitis, cerebral infarction,transient ischemic attack, angina pectoris, and the like.

[0100] The pharmaceutical composition of this invention can be used inthe form of a pharmaceutical preparation, for example, in a solid,semisolid or liquid form, which contains the pyrazolo-pyrazine compound(I) or a pharmaceutically acceptable salt thereof as an activeingredient in admixture with an organic or inorganic carrier orexcipient suitable for rectal, pulmonary (nasal or buccal inhalation),nasal, ocular, external (topical), oral or parenteral (includingsubcutaneous, intravenous and intramuscular) administrations orinsufflation. The active ingredient may be compounded, for example, withthe usual non-toxic, pharmaceutically acceptable carriers for tablets,pellets, troches, capsules, suppositories, creams, ointments, aerosols,powders for insufflation, solutions, emulsions, suspensions, and anyother form suitable for use. In addition, auxiliary, stabilizing agents,thickening agents, coloring agents and perfumes may be used wherenecessary. The pyrazolopyrazine compound (I) or a pharmaceuticallyacceptable salt thereof is included in a pharmaceutical composition inan amount sufficient to produce the desired aforesaid pharmaceuticaleffect upon the process or condition of diseases.

[0101] For applying the composition to a human being or an animal, it ispreferable to apply it by intravenous, intramuscular, pulmonary or oraladministration, or insufflation. While the dosage of therapeuticallyeffective amount of the pyrazolo-pyrazine compound (I) varies dependingon the age and condition of each individual patient to be treated, inthe case of intravenous administration, a daily dose of 0.01-100 mg ofthe pyrazolo-pyrazine compound (I) per kg weight of a human being or ananimal, in the case of intramuscular administration, a daily dose of0.1-100 mg of the pyrazolopyrazine compound (I) per kg weight of a humanbeing or an animal, and in case of oral administration, a daily dose of0.5-100 mg of the pyrazolopyrazine compound (I) per kg weight of a humanbeing or an animal is generally given for the prevention and/ortreatment of the aforesaid diseases.

[0102] The following Preparations and Examples are given for the purposeof illustrating the present invention in more detail.

[0103] Preparation 1

[0104] To a solution of 2,5-dibromopyridine (12.0 g) and thiophenol(5.46 mL) in DME (50 mL) was added sodium tert-butoxide (5.35 g) at roomtemperature and the mixture was stirred at 100° C. for 15 h. Thereaction mixture was poured into brine, extracted with EtOAc, washedwith brine, dried over sodium sulfate, evaporated in vacuo. The residuewas purified by silica gel column chromatography (n-hexane-EtOAc 30:1)to give 5-bromo-2-(phenylsulfanyl)pyridine (13.69 g) as an oil.

[0105] IR (neat) 3055, 1554, 1475, 1441, 1352 cm⁻¹ ¹H NMR (DMSO-d₆) δ6.92 (1H, dd, J=8.6, 0.5 Hz), 7.45-7.65 (5H, m), 7.89 (1H, dd, J=8.6,2.5 Hz), 8.54 (1H, d, J=2.5 Hz) APCI-MS m/z 266, 268 (MH⁺).

[0106] Preparation 2

[0107] To a solution of 5-bromo-2-(phenylsulfanyl)pyridine (12.9 g) inCH₂Cl₂ (500 mL) was added 70% mCPBA (24.0 g) at 5° C. and the mixturewas stirred at room temperature for 4.5 h. The reaction mixture wasconcentrated in vacuo, diluted with EtOAc, washed with a mixture of10%Na₂S₂O₃ and saturated sodium hydrogen carbonate, water, and brine,dried over sodium sulfate, evaporated in vacuo to give5-bromo-2-(phenylsulfonyl)pyridine (13.7 g) as a crystaline solid.

[0108] IR (KBr) 3107, 3059, 1579, 1562, 1545, 1442, 1356, 1327 cm⁻¹ ¹HNMR (DMSO-d₆) δ 7.58-7.82 (3H, m), 7.93-8.02 (2H, m), 8.16 (1H, dd,J=8.4, 0.6 Hz), 8.42 (1H, dd, J=8.4, 2.3 Hz), 8.87 (1H, dd, J=2.3, 0.6Hz) APCI-MS m/z 298, 300 (MH⁺).

[0109] Preparation 3

[0110] To a mixture of 5-bromo-2-(phenylsulfonyl)pyridine (6.00 g),ethynylbenzene (2.87 mL), dichlorobis(triphenylphosphine)palladium (II)(140 mg) and CuI (38 mg) in DMF (90 mL) was added triethylamine (8.42mL) and the mixture was stirred at 60° C. for 1 h. The reaction mixturewas diluted with EtOAc, washed with water and brine, dried over sodiumsulfate, evaporated in vacuo. The residue was purified by silica gelcolumn chromatography (CHCl₃ to CHCl₃—EtOAc 10:1) to give5-(phenylethynyl)-2-(phenylsulfonyl)pyridine (6.33 g) as a solid.

[0111] IR (KBr) 3057, 2220, 1568, 1487, 1446, 1362, 1333 cm⁻¹ ¹H NMR(DMSO-d₆) δ 7.40-7.83 (5H, m), 7.95-8.05 (2H, m), 8.23-8.36 (2H, m),8.87 (1H, dd, J=1.9, 0.9 Hz) APCI-MS m/z 320 (MH⁺).

[0112] Preparation 4

[0113] To a mixture of 5-(phenylethynyl)-2-(phenylsulfonyl) pyridine(6.00 g) and K₂CO₃ (13.0 g) in DMF (120 mL) was added1-aminopyrazin-1-ium iodide (12.6 g) and the mixture was stirred at roomtemperature for 1 h, then stirred at 60° C. for 8 h. To the reactionmixture was added K₂CO₃ (7.80 g) and 1-aminopyrazin-1-ium iodide (8.38g) and stirred at room temperature for 1 h, then stirred at 60° C. for12 h. To the reaction mixture was added further K₂CO₃ (7.80 g) and1-aminopyrazin-1-ium iodide (8.38 g) and stirred at room temperature for1 h, then stirred at 60° C. for 26 h. The mixture was poured into icewater and extracted with EtOAc, washed with water and brine, dried oversodium sulfate, evaporated in vacuo. The residue was purified by silicagel column chromatography (n-hexane-EtOAc 3:1 to CHCl₃—MeOH 20:1) togive 2-phenyl-3-[6-(phenylsulfonyl)-3-pyridinyl]pyrazolo[1,5-a] pyrazine(4.14 g) as an amorphous solid.

[0114] IR (KBr) 1581, 1522, 1446, 1315 cm⁻¹ ¹H NMR (DMSO-d₆) δ 7.30-7.55(5H, m), 7.55-7.83 (3H, m), 7.90-8.20 (3H, m), 8.20-8.32 (2H, m),8.67-8.75 (1H, m), 8.92 (1H, dd, J=4.8, 1.4 Hz), 9.23 (1H, d, J=1.4 Hz)

[0115] APCI-MS m/z 413 (MH⁺).

[0116] Preparation 5

[0117] A mixture of2-phenyl-3-[6-(phenylsulfonyl)-3-pyridinyl]pyrazolo[1,5-a]pyrazine (3.93g) and sodium methoxide (5.2M MeOH solution, 10 mL) in MeOH (60 mL) and1,4-dioxane (60 mL) was stirred at 85° C. for 1 h. The reaction mixturewas concentrated in vacuo, and ice water was added, extracted, withEtOAc, washed with water and brine, dried over sodium sulfate,evaporated in vacuo. The residue was purified by silica gel columnchromatography (n-hexane-EtOAc 2:3) to give3-(6-methoxy-3-pyridinyl)-2-phenylpyrazolo[1,5-a]pyrazine (2.37 g) as anoil.

[0118] IR (neat) 3049, 2945, 1606, 1535, 1498, 1481, 1462, 1369 cm⁻¹ ¹HNMR (DMSO-d₆) δ 3.91 (3H, s), 6.92 (1H, d, J=8.5 Hz), 7.35-7.60 (5H, m),7.72 (1H, dd, J=8.5, 2.4 Hz), 7.99 (1H, d, J=4.9 Hz), 8.26 (1H, d, J=2.4Hz), 8.86 (1H, dd, J=4.9, 1.4 Hz), 9.06 (1H, d, J=1.4 Hz) APCI-MS m/z303 (MH⁺).

[0119] Preparation 6

[0120] 5-[(4-Fluorophenyl)ethynyl]-2-(phenylsulfonyl)pyridine wasobtained in a similar manner to that of Preparation 3.

[0121] IR (KBr) 3062, 2222, 2599, 1568, 1508, 1446, 1321 cm⁻¹ ¹H NMR(DMSO-d₆) δ 7.25-7.40 (2H, m), 7.58-7.80 (5H, m), 7.92-8.05 (2H, m),8.20-8.35 (2H, m), 8.86 (1H, dd, J=1.8, 0.9 Hz) APCI-MS m/z 338 (MH⁺).

[0122] Preparation 7

[0123] 2-(4-Fluorophenyl)-3-[6-(phenylsulfonyl)-3-pyridinyl]pyrazolo[1,5-a]pyrazine was obtained in a similar manner to that ofPreparation 4.

[0124] IR (KBr) 3051, 1602, 1583, 1525, 1466, 1444, 1319 cm⁻¹ ¹H NMR(DMSO-d₆) δ 7.20-7.35 (2H, m), 7.45-7.58 (2H, m), 7.60-7.80 (3H, m),7.95-8.10 (3H, m), 8.10-8.29 (2H, m), 8.71-8.78 (1H, m), 8.91 (1H, dd,J=4.7, 1.4 Hz), 9.23 (1H, d, J=1.4 Hz) APCI-MS m/z 431 (MH⁺)

[0125] Preparation 8

[0126] 2-(4-Fluorophenyl)-3-(6-methoxy-3-pyridinyl)pyrazolo[1,5-a]pyrazine-was obtained in a similar manner to that of Preparation5.

[0127] IR (KBr) 3095, 3016, 1606, 1533, 1498, 1462, 1367 cm⁻¹ ¹H NMR(DMSO-d₆) δ 3.91 (3H, s), 6.93 (1H, dd, J=8.6, 0.6 Hz), 7.20-7.35 (2H,m), 7.53-7.65 (2H, m), 7.72 (1H, dd, J=8.6, 2.5 Hz), 8.00 (1H, d, J=4.7Hz), 8.27 (1H, d, J=2.5 Hz), 8.86 (1H, dd, J=4.7, 1.4 Hz), 9.06 (1H, d,J=1.4 Hz) APCI-MS m/z 321 (MH⁺).

[0128] Preparation 9

[0129] 5-[(2-Fluorophenyl)ethynyl]-2-(phenylsulfonyl)pyridine wasobtained in a similar manner to that of Preparation 3.

[0130] IR (KBr) 2225, 1572, 1493, 1444, 1323 cm⁻¹ ¹H NMR (DMSO-d₆) δ7.25-7.47 (2H, m) , 7.47-7.82 (5H, m) , 7.94-8.06 (2H, m), 8.26 (1H, dd,J=8.1, 0.8 Hz), 8.34 (1H, dd, J=8.1, 2.0 Hz), 8.88 (1H, dd, J=2.0, 0.8Hz)

[0131] APCI-MS m/z 338 (MH⁺).

[0132] Preparation 10

[0133] 2-(2-Fluorophenyl)-3-[6-(phenylsulfonyl)-3-pyridinyl]pyrazolo[1,5-a]pyrazine was obtained in a similar manner to that ofPreparation 4.

[0134] IR (KBr) 3093, 1585, 1531, 1469, 1448, 1317 cm⁻¹ ¹H NMR (DMSO-d₆)δ 7.21-7.41 (2H, m) , 7.47-7.81 (5H, m) , 7.95-8.05 (2H, m), 8.05-8.27(3H, m), 8.69 (1H, d, J=1.5 Hz), 8.95 (1H, dd, J=4.7, 1.4 Hz), 9.35 (1H,d, J=1.4 Hz) APCI-MS m/z 431 (MH⁺).

[0135] Preparation 11

[0136] 2-(2-Fluorophenyl)-3-(6-methoxy-3-pyridinyl)pyrazolo[1,5-a]pyrazine was obtained in a similar manner to that of Preparation5.

[0137]¹H NMR (DMSO-d₆) δ 3.87 (3H, s), 6.86 (1H, dd, J=8.5, 0.4 Hz),7.20-7.40 (2H, m), 7.45-7.71 (3H, m), 8.03 (1H, d, J=4.8 Hz), 8.18 (1H,d, J=1.9 Hz), 8.89 (1H, dd, J=4.8, 1.4 Hz), 9.20 (1H, d, J=1.4 Hz)ESI-MS m/z 321 (MH⁺)

EXAMPLE 1

[0138] A mixture of 3-(6-methoxy-3-pyridinyl)-2-phenylpyrazolo[1,5-a]pyrazine (2.36 g) and concd. HCl (7.8 mL) in 1,4-dioxane (48 mL)was stirred at 100° C. for 1 h. After cooling to room temperature, tothe reaction mixture was added 5N sodium hydroxide solution and adjustedto pH 8, extracted with EtOAc, washed with brine, dried over sodiumsulfate, evaporated in vacuo. The resulting solid was collected byfiltration and washed with ether to give3-(2(1H)-pyridinon-5-yl)-2-phenylpyrazolo[1,5-a] pyrazine (1.95 g) as asolid.

[0139] mp: >250° C. IR (KBr) 1664, 1631, 1549, 1464, 1335, 1252 cm⁻¹ ¹HNMR (DMSO-d₆) δ 6.40 (1H, d, J=9.4 Hz), 7.34 (1H, dd, J=9.4, 2.6 Hz),7.39-7.53 (3H, m), 7.55 (1H, d, J=2.6 Hz), 7.60-7.72 (2H, m), 7.96 (1H,d, J=4.7 Hz), 8.82 (1H, dd, J=4.7, 1.4 Hz), 9.08 (1H, d, J=1.4 Hz),11.84 (1H, br s) APCI-MS m/z 289 (MH⁺).

EXAMPLE 2

[0140] To a suspension of3-(2(1H)-pyridinon-5-yl)-2-phenylpyrazolo[1,5-a]pyrazine (120 mg) in DMF(3 mL) was added NaH (60% oil suspension, 25 mg) at room temperature andthe mixture was stirred at the same temperature for 10 min. To themixture was added iodomethane (0.039 mL). After stirring at roomtemperature for 15 h, the reaction mixture was poured into 10% NaClsolution, extracted with EtOAc, washed with 10% NaCl solution and brine,dried over sodium sulfate, evaporated in vacuo. The residue was purifiedby silica gel column chromatography (EtOAc to CH₂Cl₂—MeOH 10:1) to give3-(1-methyl-2(1H)-pyridinon-5-yl)-2-phenylpyrazolo[1,5-a]pyrazine (114.5mg) as a solid.

[0141] mp: 168-169° C. (CH₂Cl₂-hexane) IR (KBr) 3030, 1662, 1595, 1523,1468 cm⁻¹ ¹H NMR (CDCl₃) δ 3.60 (3H, s), 6.66 (1H, d, J=9.4 Hz), 7.32(1H, dd, J=9.4, 2.6 Hz), 7.35-7.48 (4H, m), 7.60-7.75 (2H, m), 7.93 (1H,d, J=4.8 Hz), 8.40 (1H, dd, J=4.8, 1.4 Hz), 8.98 (1H, d, J=1.4 Hz)APCI-MS m/z 303 (MH⁺)

EXAMPLE 3

[0142] 3-(1-Isopropyl-2(1H)-pyridinon-5-yl)-2-phenylpyrazolo[1,5-a]pyrazine was obtained in a similar manner to that of Example 2.

[0143] mp: 196-197° C. (CH₂Cl₂-hexane) IR (KBr) 2976, 1658, 1593, 1516,1466 cm⁻¹ ¹H NMR (CDCl₃) δ 1.26 (6H, d, J=6.8 Hz), 5.31 (1H, hept, J=6.8Hz), 6.67 (1H, dd, J=9.1, 0.6 Hz), 7.27-7.49 (5H,m), 7.57-7.72 (2H, m),7.93 (1H, d, J=4.7 Hz), 8.40 (1H, dd, J=4.7, 1.4 Hz), 8.99 (1H, d, J=1.4Hz) APCI-MS m/z 331 (MH⁺).

EXAMPLE 4

[0144] 3-(1-Ethyl-2 (1H) -pyridinon-5-yl)-2-phenylpyrazolo[1,5-a]pyrazine was obtained in a similar manner to that of Example 2.

[0145] mp 192-193° C. (EtOAc) IR (KBr) 3041, 2993, 1666, 1593, 1527 cm⁻¹¹H NMR (CDCl₃) δ 1.35 (3H, t, J=7.2 Hz), 4.01 (2H, q, J=7.2 Hz), 6.66(1H, d, J=10.1 Hz), 7.30-7.50 (5H, m), 7.60-7.75 (2H, m), 7.93 (1H, d,J=4.7 Hz), 8.40 (1H, dd, J=4.7, 1.4 Hz), 8.99 (1H, d, J=1.4 Hz) APCI-MSm/z 317 (MH⁺)

EXAMPLE 5

[0146] 3-(1-n-Propyl-2(1H)-pyridinon-5-yl)-2-phenylpyrazolo[1,5-a]pyrazine was obtained in a similar manner to that of Example 2.

[0147] mp: 165-166° C. (CH₂Cl₂-hexane) IR (KBr) 3030, 2962, 2871, 1660,1599, 1522, 1466, 1437 cm⁻¹ ¹H NMR (CDCl₃) δ 0.95 (3H, t, J=7.4 Hz),1.65-1.90 (2H, m), 3.92 (2H, t, J=7.3 Hz), 6.66 (1H, d, J=10.3 Hz),7.26-7.55 (5H, m), 7.57-7.75 (2H, m), 7.93 (1H, d, J=4.8 Hz), 8.40 (1H,dd, J=4.8, 1.1 Hz), 8.98 (1H, d, J=1.1 Hz) APCI-MS m/z 331 (MH⁺).

EXAMPLE 6

[0148]3-(2(1H)-Pyridinon-5-yl)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyrazine wasobtained in a similar manner to that of Example 1.

[0149] IR (KBr) 1660, 1620, 1529, 1493 cm⁻¹ ¹H NMR (DMSO-d₆) δ 6.41 (1H,d, J=9.1 Hz), 7.25-7.40 (3H, m), 7.56 (1H, d, J=2.2 Hz), 7.60-7.75 (2H,m), 7.97 (1H, d, J=4.8 Hz), 8.81 (1H, dd, J=4.8, 1.4 Hz), 9.07 (1H, d,J=1.4 Hz), 11.84 (1H, br s) APCI-MS m/z 307 (MH⁺).

EXAMPLE 7

[0150] 3-(1-Methyl-2(1H)-pyridinon-5-yl)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyrazine was obtained in a similar manner to that ofExample 2.

[0151] mp: 222-223° C. (EtOAc) IR (KBr) 3093, 1678, 1622, 1601, 1535,1466 cm⁻¹ ¹H NMR (CDCl₃) δ 3.60 (3H, s), 6.67 (1H, d, J=9.3 Hz),7.05-7.17 (2H, m), 7.30 (1H, dd, J=9.3, 2.5 Hz), 7.39 (1H, d, J=2.5 Hz),7.60-7.72 (2H, m), 7.94 (1H, d, J=4.7 Hz), 8.38 (1H, dd, J=4.7, 1.4 Hz),8.97 (1H, d, J=1.4 Hz) APCI-MS m/z 321 (MH⁺).

EXAMPLE 8

[0152] 3-(1-Isopropyl-2(1H)-pyridinon-5-yl)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyrazine was obtained in a similar manner to that ofExample 2.

[0153] mp: 214-215° C. (EtOAc) IR (KBr) 2985, 1658, 1595, 1527, 1516cm⁻¹ ¹H NMR (CDCl₃) δ 1.29 (6H, d, J=6.8 Hz), 5.32 (1H, hept, J=6.8 Hz),6.68 (1H, d, J=10.0 Hz), 7.05-7.18 (2H, m), 7.28-7.38 (2H, m), 7.59-7.70(2H, m), 7.94 (1H, d, J=4.7 Hz), 8.39 (1H, dd, J=4.7, 1.4 Hz), 8.98 (1H,d, J=1.4 Hz) APCI-MS m/z 349 (MH⁺).

EXAMPLE 9

[0154] 3-(1-Ethyl-2(1H)-pyridinon-5-yl)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyrazine was obtained in a similar manner to that ofExample 2.

[0155] mp: 165-166° C. (EtOAc) IR (KBr) 1662, 1601, 1529, 1469, 1329cm⁻¹ ¹H NMR (CDCl₃) δ 1.37 (3H, t, J=7.2 Hz), 4.02 (2H, q, J=7.2 Hz),6.67 (1H, d, J=10.0 Hz), 7.05-7.18 (2H, m), 7.26-7.38 (2H, m), 7.60-7.73(2H, m), 7.94 (1H, d, J=4.7 Hz), 8.39 (1H, dd, J=4.7, 1.4 Hz), 8.98 (1H,d, J=1.4 Hz) APCI-MS m/z 335 (MH⁺).

EXAMPLE 10

[0156] 3-(1-n-Propyl-2(1H)-pyridinon-5-yl)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyrazine was obtained in a similar manner to that ofExample 2.

[0157] mp 183-184° C. (EtOAc) IR (KBr) 1670, 1602, 1525, 1493, 1468 cm⁻¹¹H NMR(CDCl₃) δ 0.96 (3H, t, J=7.4 Hz), 1.66-1.90 (2H, m), 3.93 (2H, t,J=7.3 Hz), 6.67 (1H, d, J=10.2 Hz), 7.03-7.18 (2H, m), 7.22-7.37 (2H,m), 7.58-7.73 (2H, m), 7.93 (1H, d, J=4.7 Hz), 8.38 (1H, dd, J=4.7, 1.4Hz), 8.97 (1H, d, J=1.4 Hz) APCI-MS m/z 349 (MH⁺).

EXAMPLE 11

[0158]3-(2(1H)-Pyridinon-5-yl)-2-(2-fluorophenyl)pyrazolo[1,5-a]pyrazine wasobtained in a similar manner to that of Example 1.

[0159] IR (KBr) 1658, 1622, 1549, 1468, 1435 cm⁻¹ ¹H NMR (DMSO-d₆) δ6.34 (1H, d, J=9.3 Hz), 7.25-7.65 (6H, m), 8.00 (1H, d, J=4.8 Hz), 8.84(1H, dd, J=4.8, 1.4 Hz), 9.18 (1H, d, J=1.4 Hz), 11.74 (1H, br s)APCI-MS m/z 307 (MH⁺).

EXAMPLE 12

[0160] 3-(1-Methyl-2(1H)-pyridinon-5-yl)-2-(2-fluorophenyl)pyrazolo[1,5-a]pyrazine was obtained in a similar manner to that ofExample 2.

[0161] mp: 193-194° C. (EtOAc) IR (KBr) 1670, 1597, 1531, 1514, 1468cm⁻¹ ¹H NMR (CDCl₃) δ 3.55 (3H, s), 6.60 (1H, d, J=9.1 Hz), 7.07-7.37(4H, m), 7.37-7.60 (2H, m), 7.96 (1H, d, J=4.8 Hz), 8.42 (1H, dd, J=4.8,1.4 Hz), 9.06 (1H, d, J=1.4 Hz) APCI-MS m/z 321 (MH⁺).

EXAMPLE 13

[0162] 3-(1-Isopropyl-2(1H)-pyridinon-5-yl)-2-(2-fluorophenyl)pyrazolo[1,5-a]pyrazine was obtained in a similar manner to that ofExample 2.

[0163] mp: 150-151° C. (EtOAc-Et₂O) IR (KBr) 2978, 1660, 1593, 1518,1468, 1446 cm⁻¹ ¹H NMR (CDCl₃) δ 1.19 (6H, d, J=6.8 Hz), 5.27 (1H, hept,J=6.8 Hz), 6.63 (1H, dd, J=9.3, 0.4 Hz), 7.07-7.60 (6H, m), 7.96 (1H, d,J=4.8 Hz), 8.42 (1H, dd, J=4.8, 1.4 Hz), 9.07 (1H, d, J=1.4 Hz) APCI-MSm/z 349 (MH⁺).

EXAMPLE 14

[0164] 3-(1-Ethyl-2(1H)-pyridinon-5-yl)-2-(2-fluorophenyl)pyrazolo[1,5-a]pyrazine was obtained in a similar manner to that ofExample 2.

[0165] mp: 173-174° C. (EtOAc) IR (KBr) 1666, 1597, 1531, 1468 cm⁻¹ ¹HNMR (CDCl₃) δ 1.29 (3H, t, J=7.2 Hz), 3.96 (2H, q, J=7.2 Hz), 6.61 (1H,dd, J=9.3, 0.5 Hz), 7.07-7.36 (4H, m), 7.36-7.60 (2H, m), 7.96 (1H, d,J=4.8 Hz), 8.42. (1H, dd, J=4.8, 1.4 Hz), 9.06 (1H, d, J=1.4 Hz) APCI-MSm/z 335 (MH⁺).

EXAMPLE 15

[0166] 3-(1-n-Propyl-2(1H)-pyridinon-5-yl)-2-(2-fluorophenyl)pyrazolo[1,5-a]pyrazine was obtained in a similar manner to that ofExample 2.

[0167] mp: 127-128° C. (EtOAc-Et₂₀) IR (KBr) 2972, 2921, 1662, 1599,1523, 1466, 1441 cm⁻¹ ¹H NMR (CDCl₃) δ 0.89 (3H, t, J=7.5 Hz), 1.60-1.83(2H, m), 3.88 (2H, t, J=7.2 Hz), 6.61 (1H, d, J=9.3 Hz), 7.06-7.35 (4H,m), 7.35-7.60 (2H, m), 7.96 (1H, d, J=4.8 Hz), 8.42 (1H, dd, J=4.8, 1.4Hz), 9.05 (1H, d, J=1.4 Hz) APCI-MS m/z 349 (MH⁺).

1. A pyrzoilopyrazine compound of the following formula (I).

wherein R¹ is hydrogen or a suitable substituent; and R² is hydrogen orhalogen, or a salt thereof.
 2. A compound of claim 1, wherein R¹ ishydrogen, lower alkyl, ar(lower)alkyl or cyclo(lower)alkyl which may beinterrupted by an oxygen atom; and R² is hydrogen or halogen.
 3. Aprocess for the preparation of the pyrazolopyrazine compound of claim 1or a salt thereof, which comprises, (1) hydrolyzing a compound of theformula (II):

wherein R² is hydrogen or halogen; R³ is lower alkyl; or a salt thereof,to give a compound of the formula (Ia):

wherein R² is as defined above or a salt thereof, (2) reacting acompound of the formula (Ia) or a salt thereof, with a compound of theformula (III): R^(1a)—X   (III) wherein R^(1a) is a suitablesubstituent, and X is a leaving group, or a salt thereof to give acompound of the formula (Ib):

wherein R^(1a) and R² are as defined above or a salt thereof.
 4. Apharmaceutical composition comprising the compound of claim 1 or apharmaceutically acceptable salt thereof in admixture with apharmaceutically acceptable carrier.
 5. A method for preventing ortreating a disease selected from the group consisting of depression,dementia, Parkinson's disease, anxiety, pain, cerebrovascular disease,heart failure, hypertension, circulatory insufficiency,post-resuscitation, asystole, braayarrhythmia, electromechanicaldissociation, hemodynamic collapse, SIRS (systemic inflammatory responsesyndrome), multiple organ failure, renal failure (renal insufficiency),renal toxicity, nephrosis, nephritis, edema, obesity, bronchial asthma,gout, hyperuricemia, sudden infant death syndrome, immunosuppression,diabetes, ulcer, pancreatitis, Meniere's syndrome, anemia,dialysis-induced hypotension, constipation, ischemic bowel disease,ileus, myocardial infarction, thrombosis, obstruction, arteriosclerosisobliterans, thrombophlebitis, cerebral infarction, transient ischemicattack and angina pectoris, which comprises administering the compoundof claim 1 or a pharmaceutically acceptable salt thereof to a humanbeing or an animal.
 6. Use of the compound of claim 1 or apharmaceutically acceptable salt thereof as a medicament.
 7. Use of thecompound of claim 1 or a pharmaceutically acceptable salt thereof as anadenosine antagonist.
 8. Use of the compound of claim 1 or apharmaceutically acceptable salt thereof as an A₁ receptor and A₂receptor dual antagonist.
 9. A process for preparing a pharmaceuticalcomposition which comprises admixing the compound of claim 1 or apharmaceutically acceptable salt thereof with a pharmaceuticallyacceptable carrier.
 10. Use of the compound of claim 1 or apharmaceutically acceptable salt thereof for the production of apharmaceutical composition for the therapy of diseases on which anadenosine antagonist is therapeutically effective.
 11. A method forevaluation of adenosine antagonism which comprises use of compound ofclaim 1 or a pharmaceutically acceptable sat thereof.